One of the research goals highlighted in the Action Plan for Liver Disease of the National Institutes of Health is to develop means, including anti-viral antibodies, to prevent recurrence of hepatitis C virus (HCV) after liver transplantation. HCV associated liver failure is the most common indication for liver transplantation but recurren HCV invariably occurs after transplantation and can lead to rapid graft loss. The immunosuppressed liver transplant recipients tolerate the side effects of IFN- and ribavirin poorly and therefore new strategies for prevention and/or treatment of HCV in the transplant setting are urgently required. The long-term objective of this application is to develop an effective and tolerable antibody cocktail to prevent recurrent HCV, and the same treatment may also be useful in preventing infection in the cases of accidental virus exposure of healthcare/laboratory workers, or in high risk populations. The specific aims are (i) to generate human monoclonal antibodies (mAbs) to diverse conserved neutralizing viral epitopes of HCV by phage-display antibody technology; (ii) to generate highly potent HCV neutralizing antibodies by function screen; (iii) to understand the mechanisms of virus neutralization by the antibodies; (iv) to evaluate the efficacy of the mAbs in protecting a recently developed genetically humanized mouse model for HCV study upon challenges by multiple heterologous HCV genotypes. A demonstration of significant protection by the antibody or antibody cocktail would provide the scientific foundation for further investigation of this passive antibody approach in th prevention of recurrent HCV in clinical settings.